The long term objective of this proposal is to study the role of the major histocompatibility complex (MHC) in the pathogenesis of ocular cicatricial pemphigoid (0CP). Twenty-five percent of the 0CP patients can become blind and cicatricial pemphigoid (CP) is potentially fatal. Our hypothesis states that MHC genes are involved in the susceptibility to 0CP and in the production of anti-basement membrane zone (BMZ) antibodies. Our published studies demonstrated a strong association between 0CP and DQw7 (DQB1* 0301). Preliminary evidence suggest that it is also associated with drug-induced or Pseudo-0CP (P-OCP) and CP limited to the oral cavity or oral pemphigoid (0P). By using molecular methods, we will subtype the HLA-D region genes (DRB1, DQA1, DQB1, and DPB1) in patients and relatives to confirm the DQB1* 0301 association and determine specific combination of genes that might be "disease specific" in the three groups. We have developed a sensitive immunoblot assay that permits definition of specific proteins that are recognized by sera of 0CP and P-OCP but not 0P patients. It will permit determining immunodominant regions or peptides recognized by sera from 0CP, P-OCP, and 0P patients and their unaffected MHC identical relatives. By obtaining LOD scores a linkage between MHC and anti-BMZ antibody will be made. It is proposed that sequencing of the HLA-D alleles of patients, will be done to determine if there are unique disease-specific composite class II elements that might be involved in T cell recognition. Comparison of sequences between patients, antibody producing and non-producing relatives and MHC matched control will help focus on their role in anti-BMZ antibody production. This work is possible because Dr. Foster has 150 cases of 0CP and 35 cases of P-OCP and Dr. Cataldo has 53 cases of 0P, available for Dr. Ahmed's studies. Dr. Ahmed has developed the techniques of protein biochemistry and those of molecular biology necessary for DNA typing and cloning of 0CP antigens. Dr. Alper and Dr. Yunis will provide their bank of normal control data and the necessary expertise required to complete these studies. This study could make 0CP a model for understanding the role of MHC in disease susceptibility, autoantibody production and for the definition of specific peptides involved in the initiation or triggering of the autoimmune process.